CNS Lyme disease is an increasingly prevalent cause of neuropsychiatric disease in the United States. It can be difficult to diagnose, mimicking dementing syndromes or psychiatric disease. The early diagnosis of CNS Lyme disease is important because it is treatable with antibiotics; however, the optimum dose and duration of treatment has not been determined. The combination of increasing prevalence and difficulties with diagnosis and treatment make this illness of increasing importance. The pathogenesis of CNS Lyme disease remains unknown. Chronic infection of the brain with B. burgdorferi appears most likely but has not been demonstrated. The involvement of cytokines or other inflammatory molecules has been postulated. Progress has thus far been poor in understanding pathogenesis because of the lack of an adequate animal model of Lyme borreliosis. We propose to study CNS Lyme disease in a recently developed murine model of Lyme borreliosis. The major questions that will be answered by this project will be: Are behavioral changes associated with chronic infection of the brain? What areas of the brain and what cell types are involved? Is susceptibility to CNS Lyme disease genetically determined? Can different strains of the organism cause varying degrees of encephalopathy? Is increased gene expression of cytokines or other inflammatory molecules associated with infection or behavioral changes? This proposal will lead to improved understanding of the pathogenesis of neuropsychiatric disturbances in CNS Lyme disease and chronic infections in general.